Case report: Macrophage activation syndrome in a patient with Kabuki syndrome

Macrophage activation syndrome (MAS), is a severe and fatal complication of various pediatric inflammatory disorders. Kabuki syndrome (KS), mainly caused by lysine methyltransferase 2D (KMT2D; OMIM 602113) variants, is a rare congenital disorder with multi-organ deficiencies. To date, there have been no reported cases of MAS in patients with KS. This report describes a case of a 22-year-old male with Kabuki syndrome (KS) who developed MAS. This unique case not only deepens the understanding of the involvement of KMT2D in immune regulation and disease, but expands the phenotype of the adult patient to better understand the natural history, disease burden, and management of patients with KS complicated with autoimmune disorders.


Introduction
Macrophage activation syndrome (MAS) is a lethal complication of various inflammatory disorders and is often associated with primary immunodeficiencies (PIDs) (1).Kabuki syndrome (KS) is a rare congenital disorder hallmarked by dysmorphic facial features (including arched eyebrows, long palpebral fissures with eversion of the lower eyelid, and large protuberant or cupped ears), intellectual disability, growth retardation, and other structural and functional defects.Genetic anomalies in lysine methyltransferase 2D (KMT2D) and lysine demethylase 6A (KDM6A) are implicated in KS.Interestingly, although patients with KS can also exhibit impaired adaptive immunity with significant hypogammaglobulinemia and display autoimmune disorders (2,3), there are no reported cases of MAS in patients with KS.Here, we present the first report of a KS patient complicated with MAS, indicating a potential association between de novo pathogenic variants of KMT2D and MAS.

Case description
A 22-year-old Chinese Han man, clinically diagnosed with common variable immunodeficiency (CVID), was referred to the department of rheumatology and immunology in our hospital due to MAS relapse after medication withdrawal.The patient was susceptible to inspiratory infections during childhood.At the first unprovoked onset of 13, he developed a fever, recurrent respiratory infections, arthritis, and rash.Notably increased ferritin (>2000ng/ mL), aspartate aminotransferase (AST) (1930U/L), C-reactive protein (CRP) (66.34mg/L), and erythrocyte sedimentation rate (ESR) (66mm/h) were observed.He was initially diagnosed with systemic juvenile idiopathic arthritis and suspected MAS in the local hospital and treated with methylprednisolone, cyclosporin A, and hydroxychloroquine sulfate.The symptoms improved significantly, with ferritin (288.9ng/mL) and ESR (4mm/h) significantly decreasing.However, pneumocystis pneumonia occurred during steroids, combined with hypogammaglobulinemia in the context, that the patient was suspected of CVID.He began regular intravenous immunoglobulin (IVIG) therapy every three weeks while continuing methylprednisolone, cyclosporine A, and hydroxychloroquine sulfate.He remained stable and was followed up at the local hospital.
At 15, He visited the Department of Pediatrics of our hospital for further evaluation and treatment adjustment.He was considered CVID as consistently low serum IgG ranging from 3.89-4.59g/L.He continued IVIG, methylprednisolone, cyclosporin, and hydroxychloroquine sulfate, and his IgG levels were maintained at 7-8 g/L.During the following 2 years, he remained stable without fever, and regular follow-ups were mainly performed in the local hospital.He gradually discontinued methylprednisolone, cyclosporin, and hydroxychloroquine sulfate in 1.5 years.
Since the age of 17, the patient has been admitted to the local hospital every 2 years for recurrent high fever, erythema of the trunk and limbs (Figure 1A), and arthritis, while maintaining regular IVIG every 3-5 weeks as maintenance treatment.Laboratory data showed several elevated ferritin (>1650ng/mL), increased liver enzyme and decreased platelet (PLT) (<100*10 9 /L).Temporary relief was achieved and ferritin returned to normal through pulse therapy of methylprednisolone (500mg/d*3days) and gradual tapering of methylprednisolone plus cyclosporin or tacrolimus over 1-1.5 years, but symptoms recurred six months after withdrawal.
To ascertain the cause of the recurrent fever, trio-whole exome sequencing (WES) was performed and identified a pathogenic "de novo" (not present in parents and siblings) missense mutation c.15535C>T, p.Arg5179Cys in the KMT2D gene (NM_003482.3,OMIM 602113) (4,5).Additional questioning revealed that he had hypothyroidism and learning difficulties, with a family history of hypothyroidism but no autoinflammatory diseases, PID, or hemophagocytic lymphohistiocytosis (HLH).Physical examination revealed distinctive features, including arched and broad eyebrows, epicanthus, a shortened and slightly narrow nose, thick and narrow lips, large prominent cupped ears, dental abnormalities, and brachydactyly (Figures 1B-E).Facial quantitative analysis, compared to a 20-29-year-old Northern Chinese population, also revealed a classical Kabuki syndrome (KS) facial appearance characterized by a slightly shorter nose, flat nasal bridge, round and blunt nasal tip, and a small, thick mouth (see Table 1).The patient was ultimately diagnosed as KS with MAS based on diagnostic criteria (2,6,7).
He responded well to methylprednisolone pulse therapy (500mg/ d*3days), tacrolimus 1mg twice daily, and hydroxychloroquine 1mg twice daily with significant symptoms and inflammation indicators improvement (see laboratory data from 27 th , June 2023 in Table 2).He remained stable without fever while receiving gradual tapered of methylprednisolone, tacrolimus 1mg twice daily, and hydroxychloroquine sulfate 1mg twice daily, alongside regular IVIG with 25-30mg every 3-5weeks, despite low IgG (7.38g/L, reference value 8-18g/L) and IgA (0.31-0.32g/L, reference value 0.7-4.0g/L).Routine blood examination, liver and kidney function, and inflammatory indicators remained normal during the next few months (see laboratory data from 12 th , August and 12 th , November 2023 in Table 2).Figure 3 provides a timeline detailing the development of the disease and the treatments received.

Discussion
Kabuki syndrome is a rare human inborn error of immunity (IEI) involving multi-systems with an estimated frequency ranging from 1:32,000 to 1:86,000 (8,9) across different ethnicities (10-13).International consensus diagnostic criteria mainly depend on its typical dysmorphic features and pathogenic/likely pathogenic KMT2D or KDM6A variants.However, facial features of KS, most distinctive between ages 3 and 12, become challenging to identify in infants, adolescents, and adults (2,14).To address this diagnostic challenge, we utilized facial quantitative analysis to enhance the recognition of facial features in older patients and anticipate future applications of this technology for newborn screening and adjunct diagnosis in adults presenting with symptoms like growth retardation, immune deficiency, and recurrent MAS.Our anthropometric data is limited to the northern Chinese population and may have limited reference value for other populations.Multicenter studies on different populations are warranted to promote the application of this model in patients with KS.
The pathogenesis of MAS is closely linked to persistent Epstein-Barr virus (EBV), and cytomegalovirus (CMV) infection, which trigger abnormal immune stimulation, T-cell activation, and excessive cytokine secretion (1).KMT2D plays a key role in terminal B cell differentiation, including somatic hypermutation and class-switch recombination (15,16).It also epigenetically regulates the gene ITGB7, which mediates leukocyte migration to inflamed and non-inflamed regions to provide immune responses (6).KMT2D pathogenic variants lead to persistent decreased IgA and IgG levels, NK cells, reduced memory (CD27 + ), and classswitched memory B cells (IgM − ) with a predisposition to recurrent infections (15,17,18).These immunodeficiencies potentially elevate the risk of developing MAS (19).Interestingly, despite normal counts and distributions of T cells and NK cells in most patients with KS (3), our patient study observed an unusual elevation of CD8 + T, CD8 + CD28 + , CD8 + DR + , and CD8 + CD38 + .CD8 + T has been previously reported to be involved in the pathogenesis of MAS (20).Moreover, KMT2D is critical for mediating the survival of activation-induced naïve CD8 + T cells (21), and KMT2D variants in colorectal cancer have been linked to increased CD8 + T cells (22), more immune cell infiltration, and enrichment of immune-related genes and pathways (23).These findings indicated a potential link between KMT2D mutations and T-cell dysfunction, leading to MAS, which may be validated in cohort studies using more functional experiments.
KS is also closely associated with various autoimmune disorders (14, 24-26), which may increase in prevalence with age (18).In line with these findings, our patient exhibited significant elevation in antithyroid peroxidase antibodies (TPO) antibody, s-thyroid stimulating hormone (TSH), alongside decreased free tetraiodothyronine recently.KMT2D encodes for proteins acting in the COMPASS complex, involved in the epigenetic regulation of FOXP3 (27).FOXP3 is crucial to the differentiation of naïve CD4 + T cells into T-regulatory cells, which contribute to the maintenance of peripheral tolerance (3).Therefore, pathogenic KMT2D variants impair the generation, development, and differentiation of regulatory T cells (3), leading to a breakdown of T-cell tolerance, possibly explaining consequent MAS.Further investigation should focus on T cell subsets in a larger cohort of patients with KS to better elucidate the role of KMT2D in the regulation of development and pathogenesis of MAS.
Our patients achieved satisfactory disease control with combination therapy of corticosteroid, tacrolimus, and hydroxychloroquine sulfate.Tacrolimus, known for inhibiting Tcell activation in organ transplants (28), supports the role of T-cell activation in KS with concomitant MAS.Early recognition and initiation of potent immunosuppressive therapy can reduce the severity of organ complications.Despite regular intravenous immunoglobulin administration, our patient continued to exhibit low IgA levels, underscoring the need for vigilant monitoring for potential IgA antibody formation (29,30).Regular testing of  The laboratory data of MAS episode and after-treatment.AST, aspartate aminotransferase; PLT, platelet; hs-CRP, hypersensitive C-reactive protein; ESR, erythrocyte sedimentation rate; WBC, white blood cell; Ig, immunoglobulin.
immunoglobulin levels is recommended for patients with KS to ensure effective management of the disease.

Conclusions
This report describes the first case of a patient with KS concurrent with MAS.This unique case provides a clue for the association between KMT2D and MAS and the roles of KTM2D in immune regulation and disease.It also expands the phenotype of the adult patient to better understand the natural history, disease burden, and management of patients with KS complicated with autoimmune disorders.

Patient perspective
The patient and his mother were fully engaged throughout the treatment and told us that his symptoms improved significantly after treatment and remained stable recently.The patient consented to the publication of this case report and written informed consent was obtained.

1
FIGURE 1 Representative images of the patient with Kabuki syndrome.(A) Erythema during a disease flare.(B) Representative facial images of the patient.An arched eyebrow, epicanthus, short columella with a slightly narrow nose, thick and narrow lips, and prominent cupped ears were observed in the lateral view.(C) Dental anomalies.(D, E) brachydactyly.(D) Short hands with stubby fingers and dustpan-line finger creases, and short fifth digits were displayed.

TABLE 1
Facial quantitative analysis results of the patient.
Data presented as mean ± standard deviation.

TABLE 2
Latest follow-up Laboratory data of the patient.A timeline showing the development of the disease and the treatments received.